Many important biochemical compounds and drugs of natural origin contain spirofuranone ring structures (FIG. 1). There are numerous examples of these structures among the carbohydrates, terpenoids, vitamins, alkaloids, glycosides, and antibiotics. The presence of tricyclic structures in such diverse types of compounds is strongly indicative of the profound effects that such structures exert on physiological activity, which is reflected in the robust efforts to identify useful therapeutic agents that possess these characteristics.
Numerous studies have led to a wide variety of modern drugs and potential pharmaceutical candidates that share the compact tricyclic systems, such as Alliacanes (displaying antimicrobial activity and inhibition of DNA synthesis in the ascetic form of Ehrlich carcinoma), Arteannuins (antimalarial agents), Allamancins (antileukemic activity), Teucrolins (possessing a range of biological activities including antioxidant, antisepsis, anti-inflammation, antipyretic, analgesic, and antifeedant activities), and many others (FIG. 1). Such a broad natural diversity and biological activity present in a wide spectrum of these systems make them extremely attractive targets for synthetic chemists. Listed below are several distinct examples of families of natural products, which all contain multiple tricyclic angularly fused furanone frames despite having different biological origins.
From a synthetic point of view, there has been sustained interest in the chemistry of all of the above-mentioned natural products over the past few decades. Analysis of their molecular structures shows a highly compacted carbon skeleton with an angularly fused tri-penta/hexa/hepta/octa- or macro-cycles of different oxidation states in each of the rings, which together present a real synthetic challenge.
Since these molecules are naturally produced (in plants, fungi, microbes, and marine organisms) in small quantities, there is great interest in mass-producing them through a synthetic pathway. Unfortunately, access to a large number of these target molecules and their structural analogues is either unknown or hindered by their multistep syntheses. Furthermore, many compounds can only be harvested from their natural source, which is a process that can be tedious, time consuming, and expensive, as well as being wasteful on the natural resource. For example the following natural compounds have no or very tedious and commercially limited total synthesis reported Teucrolins (3 family members), Chlorahololides, Multistalides, Chloamutilides, Sarcanolides (11 members), Arteannuins (7 family members) has reported syntheses of some members (8-13 steps), Jaborosalactone, Callilongisin B, Allamancins (9 family members)—reported total synthesis of some products, Alliacanes (9 family members)—although there are numerous approaches to this natural product family, only three syntheses have been completed to date.
Though elegant and creative, the existing target-oriented strategies require harsh conditions, protecting group manipulations, and purification after each synthetic step (with overall low yields). For example, in the most recent attempt (2003) K. D. Moeller and co-workers accomplished the total synthesis of Alliacol A in 14 steps, which provided the first synthetic access to this sesquiterpenoid natural product family.
It should also be noted that the number of structural analogues that can be obtained from total synthesis or harvesting is limited. Thus, there is an urgent need for an efficient, concise, and universal protocol to provide scientist with access to a diverse range of natural and artificial structural derivatives (potential therapeutic agents and drug candidates).
There is therefore a long awaited need in the industry to provide a general or common approach towards the construction of naturally occurring complex structures such as quaternary carbon-centered tricyclic spiranoid lactones and natural and/or none natural derivatives thereof.
The present invention thus provides a common synthetic strategy using simple production steps for producing the tricyclic skeletons in a rapid and efficient manner.